Aryloxyalkylcarbamate-type derivatives, preparation method thereof and use of same in therapeutics

ABSTRACT

The invention relates to a compound of formula (I): 
                         
Wherein m, n, X, Y, R 1 , R 2 , R 3  and R 4  are as defined herein. The invention also relates to the use of same in therapeutics.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International application No.PCT/FR2005/000,028, Jan. 7, 2005, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofFrench Patent Application No. 04/00,389, filed Jan. 16, 2004.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

The invention relates to aryloxyalkyl-carbamate derivatives, to theirpreparation and to their application in therapy.

SUMMARY OF THE INVENTION

The compounds of the invention conform to the general formula (I):

in which

m represents 0, 1, 2 or 3;

n represents 0, 1, 2 or 3;

X represents an oxygen or sulfur atom or an SO or SO₂ group;

R₁ and R₂ represent independently of one another a hydrogen atom or aC₁₋₃ alkyl group, or R₁ and R₂ together form a group —(CH₂)_(p)—, wherep represents an integer ranging from 1 to 5 such that n+p is an integerranging from 2 to 5;

R₃ represents a hydrogen or fluorine atom or a hydroxyl or methyl group;

R₄ represents a group of general formula CHR₅CONHR₆ in which

R₅ represents a hydrogen atom or a C₁₋₆ alkyl group and

R₆ represents a hydrogen atom or a C₁₋₆ alkyl, C₃₋₇ cycloalkyl or C₃₋₇cycloalkyl-C₁₋₆ alkylene group;

Y represents

a group Y₁ selected from in particular a phenyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, naphthyl, quinolinyl,isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,cinnolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl,dihydrobenzothienyl, indolyl, isoindolyl, indolinyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzotriazolyl, benzoxadiazolyl and benzothiadiazolyl; the group Y₁being optionally substituted by one or more substituents Y₂, which areidentical to or different from one another, or by a group Y₃;

Y₂ represents a halogen atom or a cyano, nitro, C₁₋₈ alkyl, C₁₋₈ alkoxy,C₁₋₈ thioalkyl, C₁₋₈ fluoroalkyl, C₁₋₈ fluoroalkoxy, C₁₋₈fluorothioalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₃₋₇cycloalkyl-C₁₋₈ alkylene, C₃₋₇ cycloalkyl-C₁₋₈ alkyloxy, hydroxyl,NR₇R₈, NHCOR₇, NHSO₂R₇, COR₇, CO₂R₇, CONR₇R₈, SO₂R₇, SO₂NR₇R₈, —O—C₁₋₃alkylene)-O—, phenyloxy, phenylthio, phenyl-C₁-C₈ alkylene, phenyl-C₁-C₈alkyloxy or phenyl-C₁-C₈ alkylthio group;

Y₃ represents a group selected from in particular a phenyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl;

it being possible for the group or groups Y₃ to be substituted by one ormore groups Y₂ which are identical to or different from one another;

R₇ and R₈ represent independently of one another a hydrogen atom or aC₁₋₆ alkyl group, or with the nitrogen atom carrying them form anazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepineor piperazine ring optionally substituted by a C₁₋₃ alkyl or benzylgroup.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of general formula (I) a first group of compounds isthat for which:

Y represents

a group Y₁ selected from in particular a phenyl, pyridinyl, pyrimidinyl,thiazolyl, naphthyl, quinolinyl, isoquinolinyl and benzoxazolyl; thegroup Y₁ being optionally substituted by one or more substituents, moreparticularly by one or two substituents, Y₂, which are identical to ordifferent from one another, or by a group Y₃;

Y₂ represents a halogen atom, more particularly a chlorine, a fluorineor a bromine, a cyano, C₁₋₈ alkyl, more particularly a methyl,isopropyl, butyl, tert-butyl or tetramethylbutyl, C₁₋₈ alkoxy, moreparticularly a methoxy, ethoxy or propoxy, C₁₋₈ fluoroalkyl, moreparticularly a trifluoromethyl, C₁₋₈ fluoroalkoxy, more particularly atrifluoromethoxy, phenyloxy or phenyl-C₁-C₈ alkylene group, moreparticularly a phenyl(1,1-dimethylmethylene);

Y₃ represents a phenyl group; it being possible for Y₃ to be substitutedby one or more groups, more particularly by one or two groups, Y₂ whichare identical to or different from one another.

Among the compounds of the first group as defined above a second groupof compounds is that for which:

Y represents

a group Y₁ selected from in particular a phenyl or a naphthyl; the groupY₁ being optionally substituted by one or more substituents, moreparticularly by one or two substituents, Y₂, which are identical to ordifferent from one another, or by a group Y₃;

Y₂ represents a halogen atom, more particularly a chlorine, a fluorineor a bromine, a cyano, C₁₋₈ alkyl, more particularly a methyl,isopropyl, butyl, tert-butyl or tetramethylbutyl, C₁₋₈ alkoxy, moreparticularly a methoxy, ethoxy or propoxy, C₁₋₈ fluoroalkyl, moreparticularly a trifluoromethyl, C₁₋₈ fluoroalkoxy, more particularly atrifluoromethoxy, phenyloxy or phenyl-C₁-C₈ alkylene group, moreparticularly a phenyl(1,1-dimethylmethylene);

Y₃ represents a phenyl group; it being possible for Y₃ to be substitutedby one or more groups, more particularly by one or two groups, Y₂ whichare identical to or different from one another.

Among the compounds of general formula (I) a third group of compounds isthat for which:

m represents 0, 1, 2 or 3; and/or

n represents 0, 1, 2 or 3; and/or

R₁ and R₂ represent independently of one another a hydrogen atom or aC₁₋₃ alkyl group, or R₁ and R₂ together form a group —(CH₂)_(p)—, wherep represents an integer ranging from 1 to 5 such that n+p is an integerranging from 2 to 5;

with the proviso that, when R₁ and R₂ represent independently of oneanother a hydrogen atom or a C₁₋₃ alkyl group, m+n>1.

Among the compounds of the third group as defined above, a fourth groupof compounds is that for which:

m represents 0, 1, 2 or 3; and/or

n represents 0, 1, 2 or 3; and/or

R₁ and R₂ together form a group —(CH₂)_(p)—, where p represents aninteger ranging from 1 to 4 such that n+p is equal to 4.

Among the compounds of general formula (I), a fifth group of compoundsis that for which X represents an oxygen atom.

Among the compounds of general formula (I), a sixth group of compoundsis that for which R₃ represents a hydrogen atom.

A seventh group is formed of the compounds for which simultaneously R₁,R₂, R₃, R₄, R₅, R₆, R₇, R₈, X, Y, Y₁, Y₂, Y₃, n and m are as defined inthe subgroups of compounds above.

The compounds of general formula (I) may include one or more asymmetriccarbons. They may exist in the form of enantiomers or diastereoisomers.These enantiomers and diastereoisomers, and also mixtures thereof,including the racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or ofaddition salts with acids. Such addition salts form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids, although the salts of other acids which are of use, for example,for purifying or isolating compounds of formula (I) likewise form partof the invention. The compounds of general formula (I) may be in theform of hydrates or solvates, namely in the form of associations orcombinations with one or more molecules of water or with a solvent. Suchhydrates and solvates likewise form part of the invention.

In the context of the invention the terms are understood as follows:

-   -   C_(t-z), where t and z may take the values from 1 to 8, is a        carbon chain which may have from t to z carbon atoms; for        example, C₁₋₃ is a carbon chain which may have from 1 to 3        carbon atoms;    -   alkyl is a saturated, linear or branched aliphatic group; for        example, a C₁₋₃ alkyl group represents a linear or branched        carbon chain of 1 to 3 carbon atoms, more particularly a methyl,        ethyl, propyl or 1-methylethyl;    -   alkylene is a saturated, linear or branched divalent alkyl        group; for example, a C₁₋₃ alkylene group represents a linear or        branched, divalent carbon chain of 1 to 3 carbon atoms, more        particularly a methylene, ethylene, 1-methylethylene, propylene        or 1,1-dimethyl-methylene;    -   cycloalkyl is a cyclic alkyl group; for example, a C₃₋₅        cycloalkyl group represents a cyclic carbon group of 3 to 5        carbon atoms, more particularly a cyclopropyl, cyclobutyl or        cyclopentyl;    -   alkenylene is a divalent unsaturated aliphatic group containing        at least 2 carbons, more particularly an ethylene;    -   alkoxy is an —O-alkyl group having a saturated, linear or        branched aliphatic chain;    -   thioalkyl is an —S-alkyl group having a saturated linear or        branched aliphatic chain;    -   fluoroalkyl is an alkyl group in which one or more hydrogen        atoms have been substituted by a fluorine atom;    -   fluoroalkoxy is an alkoxy group in which one or more hydrogen        atoms have been substituted by a fluorine atom;    -   fluorothioalkyl is a thioalkyl group in which one or more        hydrogen atoms have been substituted by a fluorine atom; and    -   a halogen atom is a fluorine, a chlorine, a bromine or an        iodine.

The compounds of the invention may be prepared according to differentmethods, which are illustrated by the schemes which follow.

Thus one method of preparation (Scheme 1) consists in reacting an amineof general formula (II), in which Y, X, R₁, R₂, R₃, m and n are asdefined in the general formula (I), with a carbonate of general formula(III), in which Z represents a hydrogen atom or a nitro group, R₅ is asdefined in the general formula (I) and R represents a methyl or ethylgroup, in a solvent such as toluene or dichloroethane, at a temperatureof between 0 and 80° C. The resultant carbamate esters of generalformula (IV) are subsequently converted into compounds of generalformula (I) by aminolysis, by means of an amine of general formula R₆NH₂where R₆ is as defined in the general formula (I). The aminolysisreaction may be carried out in a solvent such as methanol or ethanol, ora mixture of solvents such as methanol and tetrahydrofuran.

Another method (Scheme 2) of obtaining the compounds of general formula(I) in which R₂ represents more particularly a hydrogen atom consists inreacting a derivative of general formula (IIa) in which W represents ahydroxyl, mesylate or tosylate group or a chlorine, bromine or iodineatom, and in which Y, X, R₁, R₃, m and n are as defined in the generalformula (I), with an oxazolidine dione of general structure (V), inwhich R₅ is as defined in the general formula (I), to give theoxazolidine dione derivative of general structure (VI). In the casewhere W represents a hydroxyl group the reaction may be conductedaccording to the conditions of Mitsunobu (Synthesis, 1981, 1-28); forexample, by the action of diethyl or diisopropyl azodicarboxylate in thepresence of triphenylphosphine. In the case where W represents achlorine, bromine or iodine atom or a mesylate or tosylate group thereaction may be conducted in the presence of a base such as1,1,3,3-tetramethylguanidine, sodium hydride or sodium tert-butoxide ina solvent such as tetrahydrofuran, acetonitrile or dimethylformamide ata temperature of between 0° C. and the reflux temperature of thesolvent. The resultant oxazolidine dione derivative of general formula(VI) is subsequently converted into a compound of general formula (I) byaminolysis, by means of an amine of general formula R₆NH₂ where R₆ is asdefined in the general formula (I).

Another variant (Scheme 3), for obtaining the compounds of generalformula (I) in which X represents more particularly an oxygen atom,consists in reacting an alcohol derivative of general formula (VIIa),(VIIb) or (VIIc) with a phenol derivative of general structure YOH, inwhich the Y is as defined in the general formula (I), for example inaccordance with the Mitsunobu reaction conditions (Synthesis, 1981,1-28) or modified conditions (Tetrahedron Letters 1993, 34, 1639-1642),the carbamate ester (IVa) and oxazolidine dione (VIa) derivatives beingsubsequently converted into compounds of general formula (I) byaminolysis reaction by means of an amine of general structure R₆NH₂where R₆ is as defined in the general formula (I).

In the general formulae (VIIa), (VIIb) and (VIIc), the groups R₁, R₂,R₃, R₅, R₆, m, n and R are as defined above.

Another variant (Scheme 4) for obtaining the compounds of generalformula (I) in which Y represents more particularly a group Y₁-Y₃ ofaryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryltype, consists in reacting an aryl halide derivative of generalstructure (VIII), in which U is a bromine or iodine atom and Y₁, X, R₁,R₂, R₃, R₅, R₆, n and m are as defined in the general formula (I), withan arylboronic or heteroarylboronic acid derivative of formula Y₃B(OH)₂,where Y₃ is as defined in the general formula (I), in accordance withthe Suzuki reaction conditions (Chem. Rev. 1995, 95, 2457-2483) or withan aryl- or heteroaryl-tri-alkylstannane derivative of formulaY₃Sn(R′)₃, where Y₃ is as defined in the general formula (I) and R′ is aC₁₋₄ alkyl, in accordance with the Stille reaction conditions (Angew.Chem. Int. Ed. 1986, 25, 504-524).

The compounds of general formulae (II), (IIa), (III), (V), (VIIa),(VIIb), (VIIc) and (VIII) and the phenol derivatives of generalstructure YOH, when the method by which they are prepared is notdescribed, are available commercially or are described in theliterature, or else may be prepared according to methods which aredescribed therein or which are known to the person skilled in the art.

The amines of general formula R₆NH₂ are available commercially.

The examples which follow illustrate the preparation of some compoundsof the invention. These examples are not limitative, and merelyillustrate the invention. The microanalyses, the IR and NMR spectraand/or the LC-MS (Liquid Chromatography coupled to Mass Spectroscopy)confirm the structures and purities of the compounds obtained.

m.p. (° C.) represents the melting point in degrees Celsius.

The numbers indicated in parentheses in the titles of the examplescorrespond to those from the 1st column of the table thereafter.

The IUPAC (International Union of Pure and Applied Chemistry)nomenclature has been used for naming the compounds in the followingexamples. For example, for the biphenyl group, the following numberinghas been respected:

EXAMPLE 1 Compound 1 2-(methylamino)-2-oxoethyl{2-[(4-chlorophenyl)-oxy]ethyl}carbamate

1.1 ethyl[(phenyloxycarbonyl)oxy]acetate

A solution of 25 g (240 mmol) of ethyl glycolate and of 55 ml (315 mmol)of diisopropylethylamine in 500 ml of toluene is admixed slowly atambient temperature with 32 ml (256 mmol) of phenyl chloroformate.Stirring is continued at ambient temperature for 2 hours. The saltformed is separated off and the filtrate is concentrated under reducedpressure. This gives 53.7 g of oily product, used as it is in thefollowing step.

1.2. ethyl {[({2-[(4-chlorophenyl)oxy]ethyl}-amino)carbonyl]oxy}acetate

A solution of 0.6 g (3.5 mmol) of [(4-chloro-phenyl)oxy]ethylamine(Chim. Ther. 1973, 8, 259-270) and 1.3 g (5.8 mmol) of ethyl[(phenyloxy-carbonyl)oxy]acetate, prepared in Step 1.1., in 30 ml oftoluene is heated at 60° C. overnight. It is evaporated to dryness andthe product is purified by chromatography on silica gel, eluting with a30/70 mixture of ethyl acetate and cyclohexane. This gives 0.7 g of oilyproduct, containing ˜10% of cyclized oxazolidine dione product, used asit is in the following step.

1.3. 2-(methylamino)-2-oxoethyl {2-[(4-chlorophenyl)oxy]ethyl}carbamate

3.5 ml (7 mmol) of a 2M solution of methylamine in tetrahydrofuran areadded to a solution of 0.7 g (2.3 mmol) ofethyl{[({2-[(4-chlorophenyl)-oxy]ethyl}amino)carbonyl]oxy}acetate,prepared in Step 1.2., in 5 ml of methanol. The mixture is left to reactat ambient temperature overnight. It is evaporated to dryness and theresidual solid is washed with hexane and then with diisopropyl ether, togive 0.59 g of product in powder form.

Melting point (° C.): 147-149 LC-MS: M+H=287 ¹H NMR (DMSO) δ(ppm): 7.75(m, 1H), 7.40 (m, 1H), 7.25 (d, 2H), 6.95 (d, 2H), 4.35 (s, 2H), 3.95(t, 2H), 3.35 (m, 2H), 2.60 (d, 3H).

EXAMPLE 2 Compound 112-amino-2-oxoethyl(2-[(4-cyanophenyl)oxy]ethyl)-carbamate 2.13-(2-hydroxyethyl)-1,3-oxazolidine-2,4-dione

A solution of 3 ml (39.6 mmol) of methyl glycolate in 25 ml oftetrahydrofuran is added dropwise over 2 hours to a solution of 49 ml(95 mmol) of phosgene, 1.9M in toluene, which is diluted in 50 ml oftetrahydrofuran and cooled using an ice bath. The mixture issubsequently stirred at ambient temperature for 16 hours and evaporatedto dryness. Coevaporation is carried out 4 times with 30 ml ofdichloromethane. The residue is taken up with 40 ml of acetonitrile andadded dropwise over 1 hour to a solution of 3.4 ml (59.4 mmol) ofethanolamine and 30 ml (178 mmol) of diisopropylethylamine in a 50/10mixture of acetonitrile and dichloromethane, cooled using an ice bath.The mixture is subsequently stirred at ambient temperature for 16 hours.It is filtered over celite and evaporated to dryness and the product ispurified by chromatography on silica gel, eluting with a 70/30 then80/20 mixture of ethyl acetate and n-hexane, to give 4.9 g of product inwhite solid form.

2.2. 2-amino-2-oxoethyl(2-[(4-cyanophenyl)-oxy]ethyl)carbamate

0.61 ml (1.35 mmol) of a 2.2M solution of diethyl azodicarboxylate intoluene is added dropwise to a solution of 0.13 g (0.88 mmol) of3-(2-hydroxyethyl)-1,3-oxazolidine-2,4-dione, prepared in Step 2.1.,0.35 g (1.35 mmol) of triphenylphosphine and 0.10 g (0.89 mmol) of4-hydroxybenzonitrile in 2 ml of benzene, cooled using an ice bath. Thereaction mixture is subsequently stirred at ambient temperature for 16hours. It is evaporated to dryness and the product is purified bychromatography on silica gel, eluting with a 99/1 then 98/2 mixture ofdichloromethane and ethyl acetate. The product is taken up in 1.5 ml ofa 7M solution of ammonia (10.5 mmol) in methanol. This solution isstirred for one hour. The precipitate is filtered off and washed withethyl acetate, to give 0.035 g of white solid.

Melting point (° C.): 204-206 LC-MS: M+H=264 ¹H NMR (DMSO) δ(ppm): 7.55(d, 2H), 7.05 (m, 1H), 6.90-6.80 (m+d, 4H), 4.35 (s, 2H), 4.05 (t, 2H),3.45 (m, 2H)

EXAMPLE 3 Compound 58 2-amino-2-oxoethyl[4-(1-naphthalenyloxy]butyl]-carbamate

3.1. 3-[4-(1-naphthalenyloxy]butyl]-1,3-oxazolidine-2,4-dione

A solution of 3.1 g (11.1 mmol) of 1-[(4-bromobutyl)oxy]naphthalene(Eur. J. Med. Chem. 1997, 32, 175-179) and 1.35 g (13.3 mmol) of1,3-oxazolidine-2,4-dione (J. Med. Chem. 1991, 34, 1542-1543) in 30 mlof tetrahydrofuran is admixed dropwise with a solution of 2.55 g (22.2mmol) of 1,1,3,3-tetramethylguanidine in 15 ml of tetrahydrofuran. Themixture is heated at reflux for 8 hours. 0.28 g (2.7 mmol) of1,3-oxazolidine-2,4-dione and 0.32 g (2.7 mmol) of1,1,3,3-tetramethylguanidine are added and the mixture is heated atreflux for 4 more hours. The reaction mixture is cooled using an icebath, and 100 ml of ethyl acetate and then 50 ml of 1M aqueoushydrochloric acid are added. The system is decanted and the aqueousphase is extracted with 2×80 ml of ethyl acetate. The organic phases aresubsequently washed with 80 ml of water and then with 80 ml of saturatedaqueous sodium chloride solution. They are dried over sodium sulfate andthen evaporated to dryness. The product is purified by chromatography onsilica gel, eluting with an 80/20 mixture of cyclohexane and ethylacetate, to give 2.0 g of product, which is used as it is in thefollowing step.

3.2. 2-amino-2-oxoethyl [4-(1-naphthalenyl-oxy)butyl]carbamate

1.50 g (5.0 mmol) of3-[4-(1-naphthalenyl-oxy)butyl]-1,3-oxazolidine-2,4-dione, prepared inStep 3.1., are dissolved in a mixture of 10 ml of tetrahydrofuran and 28ml of a 7N solution of ammonia (200 mmol) in methanol. The solution isleft to react overnight at ambient temperature and then evaporated todryness. The product is purified by chromatography on silica gel,eluting with a 97/3 mixture of dichloromethane and methanol. It isrecrystallized from ethyl acetate and then washed with diethyl ether, togive 0.73 g of product in white solid form.

Melting point (° C.): 80-82 LC-MS: M+H=317 ¹H NMR (CDCl₃) δ(ppm): 8.25(dd, 1H), 7.80 (dd, 1H), 7.55-7.30 (m, 4H), 6.80 (d, 1H), 6.00 (m, 1H),5.65 (m, 1H), 5.05 (m, 1H), 4.65 (s, 2H), 4.20 (t, 2H), 3.35 (m, 2H),2.00 (m, 2H), 1.90 (m, 2H)

EXAMPLE 4 Compound 85 2-(methylamino)-2-oxoethyl4-[(4′-fluoro-4-biphenyl)-oxy]-1-piperidinecarboxylate

4.1. 1,1-dimethylethyl 4-[(4-bromophenyl)-oxy]-1-piperidinecarboxylate

A solution of 2.01 g (10 mmol) of 1,1-dimethylethyl4-hydroxy-1-piperidinecarboxylate in 20 ml of dimethylformamide isadmixed with 7 g (40 mmol) of 1-bromo-4-fluorobenzene and 2.5 g (50mmol) of sodium hydride at 50% in mineral oil. The mixture is stirred at100° C. for 3 hours and then evaporated to dryness. The residue is takenup in 50 ml of ice-water and extracted with dichloromethane. The organicextracts are evaporated to dryness, to give 3.5 g of an oily product,which is used as it is in the following step.

4.2. 4-[(4-bromophenyl)oxy]piperidine

A solution of 3.5 g (9.83 mmol) of 1,1-dimethylethyl4-[(4-bromophenyl)oxy]-1-piperidinecarbooxylate, prepared in Step 4.1.,in 20 ml of dichloromethane is admixed with 10 ml of trifluoroaceticacid and the solution is stirred at ambient temperature for 1 hour. Itis evaporated to dryness and then the residue is taken up in 30 ml oftoluene, which is evaporated again to dryness. The residue issubsequently washed with pentane and then taken up in a mixture of 60 mlof dichloromethane and 20 ml of 4N aqueous ammonia solution. It isstirred vigorously for 15 minutes and then the organic phase isdecanted, dried over sodium sulfate and evaporated to dryness, to give2.7 g of product in oil form, which is used as it is in the followingstep.

4.3. 2-(ethyloxy)-2-oxoethyl4-[(4-bromo-phenyl)oxy]-1-piperidinecarboxylate

2.7 g (7.58 mmol) of 4-[(4-bromophenyl)-oxy]piperidine, prepared in Step4.2., and 1.70 g (7.6 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}acetate,prepared in accordance with Example 1.1, are mixed in 40 ml of tolueneand the solution is heated at 50° C. for 20 hours. After cooling, it isevaporated to dryness and the product is purified by chromatography onsilica gel, eluting with a 40/60 mixture of ethyl acetate andcyclohexane. The eluate is subsequently triturated in diisopropyl ether,to give 2.9 g of product in powder form.

Melting point (° C.): 87-88

4.4. 2-(methylamino)-2-oxoethyl4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate

2.9 g (7.5 mmol) of 2-(ethyloxy)-2-oxoethyl4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate, prepared in Step 4.3.,in solution in 10 ml of a 33% ethanolic solution of methylamine arestirred at ambient temperature for 20 hours. Following evaporation, theproduct is purified by chromatography on silica gel, eluting with ethylacetate, to give 0.8 g of product in gum form, which is used as it is inthe following step.

4.5. 2-(methylamino)-2-oxoethyl4-[(4′-fluoro-4-biphenyl)oxy]-1-piperidinecarboxylate

0.1 g (0.27 mmol) of 2-(methylamino)-2-oxoethyl4-[(4-bromophenyl)oxy]-1-piperidinecarbooxylate, prepared in Step 4.4.,0.01 g of tetrakis(triphenylphosphine)palladium(0) and 0.057 g (0.4mmol) of 4-fluorophenylboronic acid are placed in a glass tube withstopper. 4 ml of toluene, 2 ml of a 2N aqueous solution of sodiumcarbonate and 0.5 ml of ethanol are added. The mixture is heated at 80°C. with stirring for 2 hours. After it has cooled, 1 ml of water and 2ml of toluene are added. The organic phase is withdrawn and the productis purified by chromatography on silica gel, eluting with a 95/5 mixtureof dichloromethane and methanol. The product is redissolved in 1 ml ofethanol and then reprecipitated by adding 2 ml of water, to give 0.031 gof product in powder form.

Melting point (° C.): 117-119 LC-MS: M+H 387 ¹H NMR (CDCl₃) δ(ppm): 7.70(dd, 2H), 7.65 (d, 2H), 7.30 (dd, 2H), 7.20 (d, 2H), 6.25 (broad s, 1H),4.80 (s+m, 3H), 4.00-3.70 (m, 4H), 3.05 (d, 3H), 2.25-2.00 (m, 4H)

EXAMPLE 5 Compound 120 2-(methylamino)-2-oxoethyl4-{[(4-bromophenyl)oxy]-methyl}-1-piperidinecarboxylate

5.1. 1,1-dimethylethyl4-{[(4-bromophenyl)-oxy]methyl}-1-piperidinecarboxylate

The procedure described in Example 4.1. is repeated. Starting from 2.5 g(11.6 mmol) of 1,1-dimethylethyl4-(hydroxymethyl)-1-piperidinecarbooxylate and 8.13 g (46.4 mmol) of1-bromo-4-fluorobenzene gives 5.75 g of crude product in oil form.

5.2. 4-{[(4-bromophenyl)oxy]methyl}piperidine

The procedure described in Example 4.2 is repeated. Starting from 5.75 gof 1,1-dimethylethyl4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate, prepared in Step5.1, gives 3 g of product in oil form.

5.3. 2-(ethyloxy)-2-oxoethyl4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate

The procedure described in Example 4.3. is repeated. Starting from 1.6 g(5.9 mmol) of 4-{[(4-bromophenyl)oxy]methyl}piperidine, prepared in Step5.2., and from 1.32 g (5.9 mmol) of ethyl{[(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example1.1., gives the product in oil form.

5.4. 2-(methylamino)-2-oxoethyl4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate

The procedure described in Example 4.4. is repeated. Starting from2-(ethyloxy)-2-oxoethyl4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate, prepared in Step5.3, gives 1.1 g of product in powder form.

Melting point (° C.): 163-165 LC-MS: M+H=386 ¹H NMR (CDCl₃) δ(ppm): 7.35(d, 2H), 6.75 (d, 2H), 6.05 (broad s, 1H), 4.70-4.50 (m, 2H), 4.30-4.10(m, 2H), 3.80 (d, 2H), 3.00-2.75 (m, 2H), 2.85 (d, 3H), 2.10-1.80 (m,3H), 1.45-1.20 (m, 2H)

EXAMPLE 6 Compound 154 2-(methylamino)-2-oxoethyl4-{[(4′-(trifluoromethyl)-4-biphenyl)oxy]methyl}-1-piperidinecarboxylate

The procedure described in Example 4.5. is repeated. Starting from 0.1 g(0,26 mmol) of 2-(methylamino)-2-oxoethyl4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarbooxylate, prepared inaccordance with Example 5, and from 0.074 g (0.389 mmol) of4-trifluoromethylphenyl-boronic acid gives 0.049 g of product in powderform.

Melting point (° C.): 197-199 LC-MS: M+H=451 ¹H NMR (DMSO) δ(ppm):7.85-7.65 (m, 7H), 7.05 (d, 2H), 4.35 (s, 2H), 4.05 (broad d, 2H), 3.90(d, 2H), 2.85 (m, 2H), 2.60 (d, 3H), 2.00 (m, 1H), 1.80 (broad d, 2H),1.35-1.10 (m, 2H).

EXAMPLE 7 Compound 137 2-amino-2-oxoethyl4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate

7.1. 1,1-dimethylethyl4-[(1-naphthalenyl-oxy)methyl]-1-piperidinecarboxylate

A solution of 5.0 g (23.2 mmol) of 1,1-dimethylethyl4-(hydroxymethyl)-1-piperidinecarbooxylate, 4.3 g (29.8 mmol) of1-naphthalenol and 7.82 g (29.8 mmol) of triphenylphosphine in 120 ml oftetrahydrofuran, cooled under nitrogen by means of an ice bath, isadmixed dropwise with a solution of 6.03 g (29.8 mmol) of diisopropylazodicarboxylate. The reaction mixture is allowed to return to ambienttemperature and stirring is continued overnight. 2 ml of methanol areadded and then the mixture is evaporated to dryness. The residue istaken up in 200 ml of dichloromethane and washed in succession with a10% aqueous potassium hydrogen sulfate solution, water and a 1M aqueoussolution of sodium hydroxide. The system is dried over sodium sulfateand evaporated to dryness. The product is purified by chromatography onsilica gel, eluting with an 80/20 then 70/30 and 50/50 mixture ofcyclohexane and dichloromethane, to give 7.96 g of product in oil form,which solidifies.

Melting point (° C): 97-100

7.2. 4-[(1-naphthalenyloxy)methyl]piperidine

A solution of 7.96 g (29.1 mmol) of 1,1-dimethylethyl4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate, prepared in Step7.1., in 120 ml of methanol and 28 ml of 35% aqueous hydrochloric acidis heated at 60° C. for 6 hours. It is cooled to ambient temperature andevaporated to dryness, and then coevaporation is carried out twice withethanol. The solid residue is washed with diethyl ether and then driedunder vacuum in the presence of phosphorus pentoxide, to give 3.1 g ofwhite solid.

The solid is taken up in 80 ml of water and a 30% aqueous sodiumhydroxide solution is added until a basic pH is obtained, after whichthe system is extracted twice with 150 ml of diethyl ether. The extractsare dried over sodium sulfate and concentrated to dryness, to give 2.75g of oily product, which is used as it is in the following step.

7.3. 2-(ethyloxy)-2-oxoethyl4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate

A solution of 2.75 g (11.4 mmol) of4-[(1-naphthalenyloxy)methyl]piperidine, prepared in Step 7.2., and 2.56g (11.4 mmol) of ethyl [(phenyloxy-carbonyl)oxy]acetate, prepared inaccordance with Example 1.1, in 80 ml of toluene is heated at 50° C.overnight. It is evaporated to dryness and the residue is taken up in amixture of water, dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic phase is decanted, dried over sodiumsulfate and evaporated to dryness. The product is purified bychromatography on silica gel, eluting with a 50/50 mixture ofcyclohexane and dichloromethane and then with dichloromethane and with a95/5 mixture of dichloromethane and ethyl acetate. This gives 2.05 g ofproduct in oil form, which is used as it is in the following step.

7.4. 2-amino-2-oxoethyl4-[(1-naphthalenyl-oxy)methyl]-1-piperidinecarboxylate

1.0 g (2.69 mmol) of 2-(ethyloxy)-2-oxoethyl4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate, prepared in Step7.3., is dissolved in 12 ml of a 7N solution of ammonia (84 mmol) inmethanol. The solution is left to react at ambient temperature for 3days. It is evaporated to dryness and the residue is purified bychromatography on silica gel, eluting with a 90/10 then 80/20, 70/30 and50/50 mixture of dichloromethane and ethyl acetate and then with a 95/5mixture of ethyl acetate and methanol. The eluate is subsequentlyrecrystallized from ethyl acetate, to give 0.77 g of product.

Melting point (° C.): 135-136 LC-MS: M+H=343 ¹H NMR (DMSO) δ(ppm): 8.15(dd, 1H), 7.80 (dd, 1H), 7.50-7.30 (m, 4H), 7.30 (m, 1H), 7.15 (m, 1H),6.95 (d, 1H), 4.35 (s, 2H), 4.15-4.00 (m+d, 4H), 4.90 (m, 2H), 2.10 (m,1H), 1.90 (d, 2H), 1.45-1.25 (m, 2H)

EXAMPLE 8 Compound 148 2-amino-2-oxoethyl4-[(7-quinolinyloxy)methyl]-1-piperidinecarboxylate

8.1. 2-(methyloxy)-2-oxoethyl 4-(hydroxymethyl)-1-piperidinecarboxylate

The procedure described in Example 2.1. is repeated, using 6.84 g (59.4mmol) of 4-(hydroxy-methyl)piperidine, in place of ethanolamine, to give7.85 g of product in colorless oil form.

8.2. 2-amino-2-oxoethyl4-[(7-quinolinyl-oxy)methyl]-1-piperidinecarboxylate

0.26 g (1.03 mmol) of 1,1′-(azodicarbonyl)-dipiperidine (ADDP) is addedto a solution of 0.16 g (0.69 mmol) of 2-(methyloxy)-2-oxoethyl4-(hydroxymethyl)-1-piperidinecarboxylate, prepared in Step 8.1., 0.26ml (1.03 mmol) of tri-n-butylphosphine and 0.13 g (0.90 mmol) of7-hydroxyquinoline in 2.5 ml of benzene, which is cooled by means of anice bath. The mixture is stirred at 0° C. for 15 minutes and then atambient temperature for 16 hours. It is filtered over celite and rinsedwith diethyl ether. The filtrates are evaporated to dryness and purifiedby chromatography on silica gel, eluting with a 70/30 mixture of ethylacetate in n-hexane. The product obtained is dissolved in 3 ml (21 mmol)of a 7M solution of ammonia in methanol. The solution is stirred for 3hours and then evaporated to dryness. The product is purified bychromatography on silica gel, eluting with a 90/10 mixture of ethylacetate in ethanol, and recrystallized from ethyl acetate, to give 0.115g of product in white solid form.

Melting point (° C.): 137-139 LC-MS: M+H=344 ¹H NMR (CDCl₃) δ(ppm): 7.80(dd, 1H), 8.05 (dd, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 7.30-7.15 (m, 2H),6.05 (m, 1H), 5.65 (m, 1H), 4.60 (s, 2H), 4.25 (m, 2H), 4.00 (d, 2H),2.90 (m, 2H), 2.10 (m, 1H), 1.95 (d, 2H), 1.50-1.30 (m, 2H)

EXAMPLE 9 Compound 168 2-(methylamino)-2-oxoethyl4-{2-[(4-bromophenyl)-oxy]ethyl}-1-piperidinecarboxylate

9.1. 1,1-dimethylethyl4-{2-[(4-bromophenyl)-oxy]ethyl}-1-piperidinecarboxylate

The procedure described in Example 4.1. is repeated. Starting from 1.93g (8.4 mmol) of 1,1-dimethylethyl4-(2-hydroxyethyl)-1-piperidinecarbooxylate and 5.88 g (33.6 mmol) of1-bromo-4-fluorobenzene gives 4.1 g of crude product in oil form.

9.2. 4-{2-[(4-bromophenyl)oxy]ethyl}-piperidine

The procedure described in Example 4.2. is repeated. Starting from1,1-dimethylethyl4-{2-[(4-bromophenyl)oxy]ethyl}-1-piperidinecarboxylate, prepared inStep 9.1., gives 1.79 g of product in powder form.

Melting point (° C.): 100-102

9.3. 2-(ethyloxy)-2-oxoethyl4-{2-[(4-bromophenyl)oxy]ethyl}-1-piperidinecarboxylate

The procedure described in Example 4.3. is repeated. Starting from 1.76g (6.19 mmol) of 4-{2-[(4 bromophenyl)oxy]ethyl} prepared in Step 9.2.,and 1.39 g (6.19 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}-acetate,prepared in accordance with Example 1.1., gives 1.4 g of product in oilform.

9.4. 2-(methylamino)-2-oxoethyl4-{2-[(4-bromophenyl)oxy]ethyl}-1-piperidinecarboxylate

The procedure described in Example 4.4. is repeated. Starting from 1.3 g(3.14 mmol) of 2-(ethyloxy)-2-oxoethyl4-{2-[(4-bromophenyl)oxy]ethyl}-1-piperidinecarboxylate, prepared inStep 9.3., gives 0.95 g of product in powder form.

Melting point (° C.): 101-103 LC-MS: M+H=400 ¹H NMR (CDCl₃) δ(ppm): 7.55(d, 2H), 7.00 (d, 2H), 6.25 (broad s, NH), 4.90-4.70 (m, 2H), 4.50-4.25(m, 2H), 4.20 (t, 2H), 3.20-2.90 (m, 2H), 3.10 (d, 3H), 2.05-1.90 (m,5H), 1.55-1.30 (m, 2H)

EXAMPLE 10 Compound 186 2-(methylamino)-2-oxoethyl4-{2-[(4′-chloro-4-biphenyl)oxy]ethyl}-1-piperidinecarboxylate

The procedure described in Example 4.5 is

repeated. Starting from 0.1 g (0.25 mmol) of 2-(methylamino)-2-oxoethyl4-{2-[(4-bromophenyl)-oxy]ethyl}-1-piperidinecarboxylate, prepared inaccordance with Example 9, and 0.117 g (0.75 mmol) of4-chlorophenylboronic acid gives 0.087 g of product in powder form.

Melting point (° C.): 104-106 LC-MS: M+H=431 ¹H NMR (CDCl₃) δ(ppm):7.70-7.50 (m, 6H), 7.10 (d, 2H) 6.20 (broad s, NH), 4.85-4.60 (m, 2H),4.45-4.15 (m, 2H), 4.20 (t, 2H), 3.15-2.95 (m, 2H), 3.05 (d, 3H),2.10-1.85 (m, 5H), 1.50-1.25 (m, 2H)

EXAMPLE 11 Compound 183 2-amino-2-oxoethyl4-[2-(7-isoquinolinyloxy)ethyl]-1-piperidinecarbamate

11.1. 2-(methyloxy)-2-oxoethyl4-(2-hydroxyethyl)-1-piperidinecarboxylate

The procedure described in Example 2.1. is repeated, using 7.6 g (59.4mmol) of 4-(2-hydroxy-ethyl)piperidine, in place of ethanolamine, togive 7.1 g of product in colorless oil form.

11.2. 2-amino-2-oxoethyl4-[2-(7-isoquinolinyloxy)ethyl]-1-piperidinecarbamate

The procedure described in Example 8.2. is repeated, starting from 0.46g (1.84 mmol) of ADDP, 0.30 g (1.24 mmol) of 2-(methyloxy)-2-oxoethyl4-(2-hydroxyethyl)-1-piperidinecarboxylate, prepared in Step 11.1., 0.46ml of tri-n-butylphosphine and 0.26 g (1.84 mmol) of7-hydroxyisoquinoline in 4 ml of benzene. The product is purified bychromatography on silica gel, eluting with ethyl acetate and then with a95/5 mixture of ethyl acetate and ethanol, to give 0.25 g of product inwhite solid form.

Melting point (° C.): 179-181 LC-MS: M+H=358 ¹H NMR (CDCl₃) δ(ppm): 9.15(s, 1H), 8.45 (d, 1H), 7.60 (d, 1H), 7.35 (dd, 1H), 7.20 (d, 1H), 6.05(m, 1H), 5.75 (m, 1H), 4.60 (s, 2H), 4.20 (t, 4H), 2.90 (m, 2H),1.90-1.70 (m, 5H), 1.40-1.20 (m, 2H)

EXAMPLE 12 Compound 83 2-amino-2-oxoethyl3-[(1-naphthalenyloxy)methyl]-1-pyrrolidinecarboxylate

12.1. 1,1-dimethylethyl3-[(1-naphthalenyl-oxy)methyl]-1-pyrrolidinecarboxylate

A solution of 1.0 g (4.9 mmol) of 1,1-dimethylethyl3-(hydroxymethyl)-1-pyrrolidinecarbooxylate (described in WO 0066557),0.95 g (6.4 mmol) of 1-naphthalenol and 1.4 g (6.9 mmol) oftri-n-butylphosphine in 40 ml of toluene and 20 ml of tetrahydrofuran,cooled under nitrogen by means of an ice bath, is admixed dropwise witha solution of 1.74 g (6.9 mmol) of ADDP. The reaction mixture is allowedto return to ambient temperature and stirring is continued for 24 hours.The mixture is filtered and the precipitate is rinsed with toluene. Itis evaporated to dryness. The residue is taken up in dichloromethane andwashed with a 1M aqueous sodium hydroxide solution. It is dried oversodium sulfate and evaporated to dryness. The residue is purified bychromatography on a silica gel column, eluting with dichloromethane andthen with a 98/2 mixture of dichloromethane and methanol, to give 0.80 gof product in colorless oil form.

12.2. 3-[(1-naphthalenyloxy)methyl]-pyrrolidine

A solution of 0.42 g (1.28 mmol) of 1,1-dimethylethyl3-[(1-naphthalenyloxy)methyl]-1-pyrrolidinecarboxylate, prepared in Step12.1., in 10 ml of 1,4-dioxane and 6 ml of a 2N solution of aqueoushydrochloric acid is stirred for 6 hours. It is evaporated to drynessand then coevaporation is carried out twice with toluene. The solidresidue is washed with diethyl ether. The solid is taken up indichloromethane and concentrated ammonia solution is added until a basicpH is obtained. The system is filtered on a Whatman PTFE cartridge andthe organic phase is concentrated, to give 0.21 g of oily product, whichis used as it is in the following step.

12.3. 2-(ethyloxy)-2-oxoethyl3-[(1-naphthalenyloxy)methyl]-1-pyrrolidinecarboxylate

A solution of 0.20 g (0.88 mmol) of3-[(1-naphthalenyloxy)methyl]pyrrolidine, prepared in Step 12.2., and0.35 g (1.5 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, prepared inaccordance with Example 1.1, in 6 ml of toluene is heated at 60° C.overnight. It is evaporated to dryness and the residue is taken up in amixture of water, dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic phase is decanted, dried over sodiumsulfate and evaporated to dryness. The residue is purified bychromatography on a silica gel column, eluting with dichloromethane andthen with a 99/1 mixture of dichloromethane and methanol. This gives0.24 g of product in oil form, which is used as it is in the followingstep.

12.4. 2-amino-2-oxoethyl3-[(1-napthalenyl-oxy)methyl]-1-pyrrolidinecarboxylate

0.24 g (0.67 mmol) of 2-(ethyloxy)-2-oxoethyl3-[(1-naphthenyloxy)methyl]-1-pyrrolidinecarboxylate, prepared in Step12.3., is dissolved in 15 ml of a 7N solution of ammonia (105 mmol) inmethanol. The solution is stirred in a stoppered tube at ambienttemperature for 3 days. It is evaporated to dryness and the residue ispurified by chromatography on a silica gel column, eluting with a 97/3then 94/6 mixture of dichloromethane and methanol. The solid obtained istriturated in diethyl ether and filtered, to give 0.15 g of product.

Melting point (° C.): 161-163 LC-MS: M+H=329 ¹H NMR (DMSO) δ(ppm): 8.15(m, 1H), 7.75 (m, 1H), 7.50-7.30 (m, 4H), 7.10-6.90 (s, 2H), 6.80 (m,1H), 4.40 (s, 2H), 4.20-4.05 (m, 2H), 3.90-3.30 (m, 4H), 2.90-2.70 (m,1H), 2.30-2.10 (m, 1H), 2.05-1.85 (m, 1H).

The table which follows lists the chemical structures and the physicalproperties of some compounds according to the invention.

TABLE (I)

m.p. ° C. Cpd Y X m n R₁ R₂ R₃ R₄ (or M + H) 1. 4-chlorophenyl O 0 1 H HH CH₂CONHCH₃ 147-149 2. 4-chlorophenyl O 0 1 H H H CH₂CONH₂ 128-130 3.4-chlorophenyl O 0 2 H H H CH₂CONH₂ 108-110 4. 4-chlorophenyl O 0 3 H HH CH₂CONH₂ 116-118 5. 3-chlorophenyl O 0 1 H H H CH₂CONH₂ 114-116 6.3-chlorophenyl O 0 2 H H H CH₂CONH₂ 90-92 7. 3-chlorophenyl O 0 3 H H HCH₂CONH₂ 114-116 8. 2-chlorophenyl O 0 1 H H H CH₂CONH₂ 128-130 9.2-chlorophenyl O 0 2 H H H CH₂CONH₂ 128-130 10. 2-chlorophenyl O 0 3 H HH CH₂CONH₂ 110-112 11. 4-cyanophenyl O 0 1 H H H CH₂CONH₂ 204-206 12.4-cyanophenyl O 0 2 H H H CH₂CONH₂ 173-175 13. 4-cyanophenyl O 0 3 H H HCH₂CONH₂ 169-171 14. 3-cyanophenyl O 0 1 H H H CH₂CONH₂ 142-143 15.3-cyanophenyl O 0 2 H H H CH₂CONH₂ 129-131 16. 3-cyanophenyl O 0 3 H H HCH₂CONH₂ 123-125 17. 4-iso-propylphenyl O 0 1 H H H CH₂CONH₂ 95-97 18.4-iso-propylphenyl O 0 2 H H H CH₂CONH₂ (295) 19. 4-iso-propylphenyl O 03 H H H CH₂CONH₂ 103-105 20. 3-iso-propylphenyl O 0 1 H H H CH₂CONH₂96-98 21. 3-iso-propylphenyl O 0 2 H H H CH₂CONH₂ (295) 22.3-iso-propylphenyl O 0 3 H H H CH₂CONH₂ 88-90 23. 4-tert-butylphenyl O 02 H H H CH₂CONH₂ 90-92 24. 4-tert-butylphenyl O 0 3 H H H CH₂CONH₂ (323)25. 3-tert-butylphenyl O 0 2 H H H CH₂CONH₂ (309) 26. 3-tert-butylphenylO 0 3 H H H CH₂CONH₂ (323) 27. 4-(1,1,3,3-tetramethylbutyl)phenyl O 0 2H H H CH₂CONH₂ (365) 28. 4-(1,1,3,3-tetramethylbutyl)phenyl O 0 3 H H HCH₂CONH₂ (379) 29. 4-(1,1-dimethylphenylmethyl)phenyl O 0 1 H H HCH₂CONH₂ (357) 30. 4-(1,1-dimethylphenylmethyl)phenyl O 0 2 H H HCH₂CONH₂ (371) 31. 4-(1,1-dimethylphenylmethyl)phenyl O 0 3 H H HCH₂CONH₂ (385) 32. 4-phenylphenyl O 0 1 H H H CH₂CONH₂ 196-198 33.4-phenylphenyl O 0 2 H H H CH₂CONH₂ 187-189 34. 4-phenylphenyl O 0 3 H HH CH₂CONH₂ 192-194 35. 4-(4-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂193-195 36. 4-(3-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂ 168-170 37.4-(2-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂ 114-116 38.4-(4-methoxyphenyl)phenyl O 0 1 H H H CH₂CONH₂ 194-196 39.4-(3-methoxyphenyl)phenyl O 0 1 H H H CH₂CONH₂ (345) 40.4-(2-methoxyphenyl)phenyl O 0 1 H H H CH₂CONH₂ 127-129 41.3-phenylphenyl O 0 1 H H H CH₂CONH₂ 126-128 42. 3-phenylphenyl O 0 2 H HH CH₂CONH₂ 110-112 43. 3-phenylphenyl O 0 3 H H H CH₂CONH₂ 127-129 44.3-(4-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂ 137-139 45.3-(3-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂ 90-92 46.3-(2-chlorophneyl)phenyl O 0 1 H H H CH₂CONH₂ 55-57 47.3-(4-methoxyphenyl)phenyl O 0 1 H H H CH₂CONH₂ 168-170 48.3-(3-methoxyphenyl)phenyl O 0 1 H H H CH₂CONH₂ 86-88 49. 2-phenylphenylO 0 1 H H H CH₂CONH₂ 92-94 50. 2-phenylphenyl O 0 2 H H H CH₂CONH₂ (329)51. 2-phenylphenyl O 0 3 H H H CH₂CONH₂ (343) 52.2-(4-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂ 130-132 53.2-(3-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂ 88-90 54.2-(2-chlorophenyl)phenyl O 0 1 H H H CH₂CONH₂ (349) 55.2-(4-methoxyphenyl)phenyl O 0 1 H H H CH₂CONH₂ 74-76 56. naphthalen-1-ylO 0 1 H H H CH₂CONH₂ (289) 57. naphthalen-1-yl O 0 2 H H H CH₂CONH₂(303) 58. naphthalen-1-yl O 0 3 H H H CH₂CONH₂ 80-82 59. naphthalen-1-ylO 0 3 H H H CH₂CONHCH₃ 90-92 60. 4-chloronaphthalen-1-yl O 0 3 H H HCH₂CONH₂ 142-144 61. 4-chloronaphthalen-1-yl O 0 3 H H H CH₂CONHCH₃108-110 62. naphthalen-2-yl O 0 1 H H H CH₂CONH₂ (289) 63.naphthalen-2-yl O 0 2 H H H CH₂CONH₂ 158-160 64. naphthalen-2-yl O 0 3 HH H CH₂CONH₂ 171-173 65. 4-phenoxyphenyl O 0 1 H H H CH₂CONH₂ 158-16066. 4-phenoxyphenyl O 0 2 H H H CH₂CONH₂ 141-143 67. 4-phenoxyphenyl O 03 H H H CH₂CONH₂ 144-146 68. pyridin-3-yl O 0 1 H H H CH₂OCNH₂ 135-13769. pyridin-3-yl O 0 2 H H H CH₂CONH₂ 119-121 70. pyridin-3-yl O 0 3 H HH CH₂CONH₂ 96-98 71. 5-chloroquinolin-8-yl O 0 1 H H H CH₂CONH₂ 232-23472. 5-chloroquinolin-8-yl O 0 2 H H H CH₂CONH₂ 183-185 73.5-chloroquinolin-8-yl O 0 3 H H H CH₂CONH₂ 184-186 74. phenyl O 1 0 H HCH₃ CH₂CONH₂ 90-92 75. 4-CF₃-phenyl O 0 2 (CH₂)₂ H CH₂CONH₂ 115-117 76.4-Cl-phenyl SO₂ 0 2 (CH₂)₂ H CH₂CONH₂ 164-166 77. 4-Cl-phenyl SO₂ 0 2(CH₂)₂ H CH₂CONHCH₃ 168-170 78. 3-CF₃-phenyl SO₂ 0 2 (CH₂)₂ H CH₂CONH₂148-150 79. 3-CF₃-phenyl SO₂ 0 2 (CH₂)₂ H CH₂CONHCH₃ 163-165 80.naphthalen-1-yl O 0 1 (CH₂)₂ H CH₂CONHCH₃ 111-113 81. naphthalen-1-yl O1 1 CH₂ H CH₂CONH₂ 176-178 82. naphthalen-1-yl O 1 1 CH₂ H CH₂CONHCH₃112-114 83. naphthalen-1-yl O 1 1 (CH₂)₂ H CH₂CONH₂ 161-163 84.naphthalen-1-yl O 1 1 (CH₂)₂ H CH₂CONHCH₃ 99-101 85.4-(4-F-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 117-119 86.4-(4-Cl-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 134-136 87.4-(4-CH₃-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 121-123 88.4-(4-n-butyl-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 105-107 89.4-(4-CF₃-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 141-143 90.4-(4-CH₃O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 152-154 91.4-(4-C₂H₅O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 145-147 92.4-(4-CF₃O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 131-133 93.4-(3-F,4-CH₃O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (417) 94.4-(3-Cl,4-F-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ 124-126 95.4-(3,4-Cl₂-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (438) 96.3-(4-F-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (387) 97.3-(4-Cl-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (403) 98.3-(4-CH₃-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (383) 99.3-(4-n-butylphenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (425) 100.3-(4-CF₃-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (437) 101.3-(4-CH₃O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (399) 102.3-(4-C₂H₅O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (413) 103.3-(4-CF₃O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (453) 104.3-(3-F,4-CH₃O-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (417) 105.3-(3-Cl,4-F-phenyl)-phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (421) 106.3-(3,4-Cl₂-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (438) 107.3-(2,4-Cl₂-phenyl)phenyl O 0 2 (CH₂)₂ H CH₂CONHCH₃ (438) 108.naphthalen-1-yl O 0 2 (CH₂)₂ H CH₂CONH₂ 137-138 109. naphthalen-1-yl O 02 (CH₂)₂ H CH₂CONHCH₃ 121-122 110. naphthalen-2-yl O 0 2 (CH₂)₂ HCH₂CONH₂ 118-120 111. quinolin-8-yl O 0 2 (CH₂)₂ H CH₂CONH₂ (330) 112.phenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 123-125 113. 4-Cl-phenyl O 1 2 (CH₂)₂ HCH₂CONH₂ 152-154 114. 4-Cl-phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 166-168 115.4-Cl-phenyl S 1 2 (CH₂)₂ H CH₂CONHCH₃ 130-132 116. 4-Cl-phenyl SO₂ 1 2(CH₂)₂ H CH₂CONHCH₃ 131-133 117. 3-Cl-phenyl O 1 2 (CH₂)₂ H CH₂CONH₂131-133 118. 3-Cl-phenyl S 1 2 (CH₂)₂ H CH₂CONHCH₃ 94-96 119.3-Cl-phenyl SO₂ 1 2 (CH₂)₂ H CH₂CONHCH₃ 100-102 120. 4-Br-phenyl O 1 2(CH₂)₂ H CH₂CONHCH₃ 163-165 121. 4-CH₃O-phenyl O 1 2 (CH₂)₂ H CH₂CONH₂128-130 122. 3-CH₃O-phenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 119-121 123.4-n-propyloxyphenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 141-143 124. 4-CF₃-phenyl O1 2 (CH₂)₂ H CH₂CONH₂ 134-136 125. 4-CF₃-phenyl S 1 2 (CH₂)₂ HCH₂CONHCH₃ 129-131 126. 4-CF₃-phenyl SO₂ 1 2 (CH₂)₂ H CH₂CONHCH₃ 103-105127. 3-CF₃-phenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 120-121 128. 3-CF₃-phenyl S 12 (CH₂)₂ H CH₂CONHCH₃ 167-169 129. 3-CF₃-phenyl SO₂ 1 2 (CH₂)₂ HCH₂CONHCH₃ 141-143 130. 4-CF₃O-phenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 118-120131. 3-CF₃O-phenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 132-134 132.4-isopropylphenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 113-115 133. 3-isopropylphenylO 1 2 (CH₂)₂ H CH₂CONH₂ 119-121 134. 2,3-Cl₂-phenyl O 1 2 (CH₂)₂ HCH₂CONHCH₃ 160-162 135. 2,4-Cl₂-phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 144-146136. 3,4-Cl₂-phenyl O 1 2 (CH₂)₂ H CH₂CONH₂ 113-115 137. naphthalen-1-ylO 1 2 (CH₂)₂ H CH₂CONH₂ 135-136 138. naphthalen-1-yl O 1 2 (CH₂)₂ HCH₂CONHCH₃ 151-152 139. naphthalen-1-yl O 1 1 (CH₂)₃ H CH₂CONH₂ 149-151140. naphthalen-1-yl O 1 1 (CH₂)₃ H CH₂CONHCH₃ (357) 141.naphthalen-1-yl S 1 2 (CH₂)₂ H CH₂CONHCH₃ 127-129 142. naphthalen-1-ylSO₂ 1 2 (CH₂)₂ H CH₂CONHCH₃ 154-156 143. naphthalen-2-yl O 1 2 (CH₂)₂ HCH₂CONH₂ 142-144 144. naphthalen-2-yl S 1 2 (CH₂)₂ H CH₂CONHCH₃ 111-113145. naphthalen-2-yl SO₂ 1 2 (CH₂)₂ H CH₂CONHCH₃ 105-107 146.4-chloronaphthalen-1-yl O 1 2 (CH₂)₂ H CH₂CONH₂ 166-168 147.4-chloronaphthalen-1-yl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 163-165 148.quinolin-7-yl O 1 2 (CH₂)₂ H CH₂CONH₂ 137-139 149. isoquinolin-7-yl O 12 (CH₂)₂ H CH₂CONH₂ 162-164 150. 4-(4-F-phenyl)phenyl O 1 2 (CH₂)₂ HCH₂CONHCH₃ 150-152 151. 4-(4-Cl-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃167-169 152. 4-(4-CH₃-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 164-166153. 4-(4-n-butyl-phenyl)-phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 171-173 154.4-(4-CF₃-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 197-199 155.4-(4-CH₃O-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 172-174 156.4-(4-C₂H₅O-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 173-175 157.4-(4-CF₃O-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 152-154 158.4-(3-F,4-CH₃O-phenyl)-phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 156-158 159.4-(3-Cl, 4-F-phenyl)-phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 132-134 160.4-(3,4-Cl₂-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 163-165 161.4-(2,4-Cl₂-phenyl)phenyl O 1 2 (CH₂)₂ H CH₂CONHCH₃ 177-179 162.pyrimidin-2-yl S 1 2 (CH₂)₂ H CH₂CONHCH₃ 109-111 163.5-phenylthiazol-2-yl S 1 2 (CH₂)₂ H CH₂CONHCH₃ (406) 164.benzoxazol-2-yl S 1 2 (CH₂)₂ H CH₂CONHCH₃ (364) 165. phenyl O 2 2 (CH₂)₂H CH₂CONH₂ 136-138 166. 4-Cl-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ 115-117 167.3-Cl-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ 91-93 168. 4-Br-phenyl O 2 2 (CH₂)₂H CH₂CONHCH₃ 101-103 169. 4-CH₃O-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ 108-110170. 3-CH₃O-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ (337) 171.4-n-propyloxy-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ 121-123 172. 4-CF₃-phenyl O2 2 (CH₂)₂ H CH₂CONH₂ 112-114 173. 3-CF₃-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂94-96 174. 4-CF₃O-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ 79-81 175.3-CF₃O-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ (391) 176. 4-isopropylphenyl O 2 2(CH₂)₂ H CH₂CONH₂ 75-77 177. 3-isopropylphenyl O 2 2 (CH₂)₂ H CH₂CONH₂(349) 178. 3,4-Cl₂-phenyl O 2 2 (CH₂)₂ H CH₂CONH₂ 103-105 179.naphthalen-1-yl O 2 2 (CH₂)₂ H CH₂CONH₂ 134-135 180. naphthalen-1-yl O 22 (CH₂)₂ H CH₂CONHCH₃ 108-109 181. naphthalen-2-yl O 2 2 (CH₂)₂ HCH₂CONH₂ (357) 182. quinolin-7-yl O 2 2 (CH₂)₂ H CH₂CONH₂ 164-166 183.isoquinolin-7-yl O 2 2 (CH₂)₂ H CH₂CONH₂ 179-181 184. 4-phenylphenyl O 22 (CH₂)₂ H CH₂CONHCH₃ 124-126 185. 4-(4-F-phenyl)phenyl O 2 2 (CH₂)₂ HCH₂CONHCH₃ 120-122 186. 4-(4-Cl-phenyl)phenyl O 2 2 (CH₂)₂ H CH₂CONHCH₃104-106 187. 4-(4-CF₃-phenyl)phenyl O 2 2 (CH₂)₂ H CH₂CONHCH₃ 137-139188. 4-(3-CF₃-phenyl)phenyl O 2 2 (CH₂)₂ H CH₂CONHCH₃ 98-100 189.4-(4-CH₃O-phenyl)phenyl O 2 2 (CH₂)₂ H CH₂CONHCH₃ 141-143 190.4-(4-CF₃O-phenyl)phenyl O 2 2 (CH₂)₂ H CH₂CONHCH₃ 116-118 191.4-(4-iso-propyl-phenyl)phenyl O 2 2 (CH₂)₂ H CH₂CONHCH₃ 121-123 192.4-(2,4-Cl₂-phenyl)phenyl O 2 2 (CH₂)₂ H CH₂CONHCH₃ 112-114

The compounds of the invention were subjected to pharmacological testspermitting determination of their inhibitory effect on the enzyme FAAH(Fatty Acid Amide Hydrolase).

The inhibitory activity was demonstrated in a radioenzymatic assay basedon measuring the product of hydrolysis (ethanolamine [1-³H]) ofanandamide [ethanolamine 1-³H] by FAAH (Life Sciences (1995), 56,1999-2005 and Journal of Pharmacology and Experimental Therapeutics(1997), 283, 729-734). Accordingly, mouse brains (minus the cerebellum)are removed and stored at −80° C. Membrane homogenates are prepared atthe time of use by homogenizing the tissues in a Polytron in a 10 mMTris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1 mM EDTA. Theenzyme reaction is subsequently conducted in 70 μl of buffer containingbovine serum albumin without fatty acids (1 mg/ml). In succession, thetest compounds, at various concentrations, anandamide [ethanolamine1-³H] (specific activity: 15-20 Ci/mmol) diluted to 10 μM with coldanandamide, and the membrane preparation (400 μg of frozen tissue perassay) are added. After 15 minutes at 25° C. the enzyme reaction isterminated by adding 140 μl of chloroform/methanol (2:1). The mixture isstirred for 10 minutes and then centrifuged for 15 minutes at 3500 g. Analiquot (30 μl) of the aqueous phase containing the ethanolamine [1-³H]is counted by liquid scintillation.

Under these conditions, the most active compounds of the inventionexhibit IC₅₀ values (concentration inhibiting by 50% the control enzymeactivity of FAAH) of between 0.001 and 1 μM. For example, compound 58 ofthe table exhibits an IC₅₀ of 0.47 μM.

It is therefore apparent that the compounds according to the inventionhave an inhibitory effect on the FAAH enzyme.

The in vivo activity of the compounds of the invention was evaluated inan analgesia test.

Accordingly, intraperitoneal (i.p.) administration of PBQ(phenylbenzoquinone, 2 mg/kg in a 0.9% sodium chloride solutioncontaining 5% of ethanol) to male OF1 mice weighing 25 to 30 g causesabdominal stretches, on average 30 twists or contractions during theperiod from 5 to 15 minutes after injection. The test compounds areadministered orally in suspension in Tween 80 at 0.5%, 60 minutes or 120minutes before the administration of PBQ. Under these conditions themost potent compounds of the invention reduce by 35 to 70% the number ofstretches induced by PBQ, within a dose range of between 1 and 30 mg/kg.For example, compound 58 of the table reduces by 51% the number ofstretches induced by PBQ, at a dose of 1 mg/kg at 2 hours.

The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121)catalyses the hydrolysis of endogenous derivatives of amides and ofesters of various fatty acids such as N-arachidonylethanolamine(anandamide), N-palmitoylethanolamine, N-oleoyl-ethanolamine, oleamideor 2-arachidonoylglycerol. These derivatives exert variouspharmacological activities by interacting, inter alia, with cannabinoidand vanilloid receptors.

The compounds of the invention block this degradation pathway andincrease the tissue level of these endogenous substances. They can beused in this respect in the prevention and treatment of pathologies inwhich endogenous cannabinoids and/or any other substrates metabolized bythe FAAH enzyme are involved.

Mention may be made, for example, of the following diseases andconditions: pain, especially acute or chronic pain of the neurogenictype: migraine, neuropathic pain, including forms associated with theherpes virus and with diabetes; acute or chronic pain associated withinflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis,spondylitis, gout, vasculitis, Crohn's disease, irritable bowelsyndrome;

-   acute or chronic peripheral pain;-   dizziness, vomiting, nausea, especially those subsequent to    chemotherapy;-   eating disorders, especially anorexia and cachexia of various kinds;-   neurological and psychiatric pathologies: shaking, dyskinesia,    dystonia, spasticity, obsessive-compulsive behaviors, Tourette's    syndrome, all forms of depression and anxiety of any kind and cause,    mood disorders, psychoses; acute and chronic neurodegenerative    diseases: Parkinson's disease, Alzheimer's disease, senile dementia,    Huntington's chorea, lesions associated with cerebral ischemia and    with cranial and medullary trauma;-   epilepsy;-   sleep disorders, including sleep apnea;-   cardiovascular diseases, especially hypertension, cardiac    arrhythmias, arteriosclerosis, heart attack, cardiac ischemias;-   renal ischemia;-   cancers: benign skin tumors, papillomas and brain tumors, prostate    tumors, brain tumors (glioblastomas, medulloepitheliomas,    medulloblastomas, neuroblastomas, tumors of embryonic origin,    astrocytomas, astroblastomas, ependyomas, oligodendrogliomas, plexus    tumor, neuroepitheliomas, epiphyseal tumor, ependymoblastomas,    malignant meningiomas, sarcomatoses, malignant melanomas,    schwannomas);-   disorders of the immune system, especially autoimmune diseases:    psoriasis, lupus erythematosis, diseases of the connective tissue or    collagen diseases, Sjögrer's syndrome, ankylosing spondylarthritis,    undifferentiated spondylarthritis, Behcet's disease, haemolytic    autoimmune anaemias, multiple sclerosis, amyotrophic lateral    sclerosis, amyloses, transplant rejection, diseases affecting the    plasmocytic line;-   allergic diseases: immediate or delayed hypersensitivity, allergic    rhinitis or conjunctivitis, contact dermatitis;-   parasitic, viral or bacterial infectious diseases: AIDS, meningitis;    inflammatory diseases, especially diseases of the joints: arthritis,    rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis,    Crohn's disease, irritable bowel syndrome;-   osteoporosis; ocular conditions: ocular hypertension, glaucoma;-   pulmonary conditions: diseases of the respiratory tracts,    bronchospasms, coughing, asthma, chronic bronchitis, chronic    obstruction of the respiratory tracts, emphysema;-   gastrointestinal diseases: irritable bowel syndrome, intestinal    inflammatory disorders, ulcers, diarrhea;-   urinary incontinence and bladder inflammation.

The use of compounds of formula (I) in base, salt, hydrate orpharmaceutically acceptable solvate form for preparing a medicinalproduct intended for treating the abovementioned pathologies forms anintegral part of the invention.

The invention likewise provides medicinal products which comprise acompound of formula (I), or a salt or else a hydrate or apharmaceutically acceptable solvate of the compound of formula (I).These medicinal products are employed in therapy, particularly in thetreatment of the abovementioned pathologies.

In accordance with another of its aspects the present invention providespharmaceutical compositions comprising as active principle at least onecompound of formula (I). These pharmaceutical compositions include aneffective dose of a compound according to the invention, or a salt or ahydrate or pharmaceutically acceptable solvate of the said compound, andoptionally one or more pharmaceutically acceptable excipients.

Said excipients are selected, according to the pharmaceutical form andthe desired mode of administration, from the customary excipients, whichare known to the person skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intrathecal, intranasal, transdermal, pulmonary, ocular or rectaladministration the active principle of formula (I) above, or its salt,solvate or hydrate where appropriate, may be administered in single-doseadministration form, in a mixture with conventional pharmaceuticalexcipients, to animals and to humans for the prophylaxis or treatment ofthe above disorders or diseases.

The unit-dose administration forms which are appropriate include oralforms such as tablets, soft or hard gelatin capsules, powders, granules,chewing gums and oral solutions or suspensions, forms for sublingual,buccal, intratracheal, intraocular and intranasal administration and foradministration by inhalation, forms for subcutaneous, intramuscular orintravenous administration and forms for rectal or vaginaladministration. For topical application the compounds according to theinvention may be used in creams, ointments or lotions.

By way of example a single-dose administration form of a compoundaccording to the invention in tablet form may comprise the followingcomponents:

Compound according to the invention 50.0 mg Mannitol 223.75 mgCroscaramellose sodium 6.0 mg Maize starch 15.0 mgHydroxypropyl-methylcellulose 2.25 mg Magnesium stearate 3.0 mg

The said single-dose forms contain a dose permitting dailyadministration of from 0.01 to 20 mg of active principle per kg ofbodyweight, depending on the pharmaceutical form.

There may be particular cases in which higher or lower dosages areappropriate; such dosages also belong to the invention. In accordancewith common practice the dosage appropriate to each patient isdetermined by the doctor according to the method of administration, theweight and the response of the said patient.

According to another of its aspects the invention also provides a methodof treating the pathologies indicated above, which comprisesadministering an effective dose of a compound according to theinvention, one of its pharmaceutically acceptable salts, or a solvate ora hydrate of the said compound.

Although the invention has been illustrated by certain of the precedingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

1. A compound of the formula (I):

wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; X is oxygen, sulfur, SO orSO₂; R₁ and R₂ are independently of one another hydrogen or C₁₋₃ alkyl;or R₁ and R₂ together form a group —(CH₂)_(p)—, where p represents aninteger ranging from 1 to 5 such that n+p is an integer ranging from 2to 5; R₃ is hydrogen, fluorine, hydroxyl or methyl; R₄ is a group offormula CHR₅CONHR₆; wherein R₅ is hydrogen or C₁₋₆ alkyl; and R₆ ishydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkyl-C₁₋₆ alkylene;and Y is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl,benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl,indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl,benzoxadiazolyl and benzothiadiazolyl; said Y is optionally substitutedby one or more substituents Y₂, which are identical to or different fromone another, or by Y₃; wherein Y₂ is halogen, cyano, nitro, C₁₋₈ alkyl,C₁₋₈ alkoxy, C₁₋₈ thioalkyl, C₁₋₈ fluoroalkyl, C₁₋₈ fluoroalkoxy, C₁₋₈fluorothioalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₃₋₇cycloalkyl-C₁₋₈ alkylene, C₃₋₇ cycloalkyl-C₁₋₈ alkyloxy, hydroxyl,NR₇R₈, NHCOR₇, NHSO₂R₇, COR₇, CO₂R₇, CONR₇R₈, SO₂R₇, SO₂NR₇R₈, —O—(C₁₋₃alkylene)-O—, phenyloxy, phenylthio, phenyl-C₁-C₈ alkylene, phenyl-C₁-C₈alkyloxy or phenyl-C₁-C₈ alkylthio group; Y₃ is selected from phenyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; said Y₃ is optionallysubstituted by one or more substituents selected from Y₂ which areidentical to or different from one another; R₇ and R₈ are independentlyof one another hydrogen or C₁₋₆ alkyl; or R₇ and R₈ with the nitrogenatom carrying them form an azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, azepine or piperazine ring optionallysubstituted by C₁₋₃ alkyl or benzyl; with the proviso that, when R₁ andR₂ are independently of one another hydrogen or C₁₋₃ alkyl, m+n>1; or asalt thereof.
 2. The compound of formula (I) according to claim 1,wherein Y is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl,naphthyl, quinolinyl, isoquinolinyl and benzoxazolyl; said Y isoptionally substituted by one or more substituents Y₂, which areidentical to or different from one another, or by Y₃; wherein Y₂ ishalogen, cyano, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ fluoroalkyl, C₁₋₈fluoroalkoxy, phenyloxy or phenyl-C₁-C₈ alkylene; and Y₃ is phenyloptionally substituted by one or more substituents selected from Y₂which are identical to or different from one another; or a salt thereof.3. The compound of formula (I) according to claim 1, wherein Y isselected from phenyl or naphthyl; said Y is optionally substituted byone or more substituents Y₂, which are identical to or different fromone another, or by Y₃; wherein Y₂ is halogen, cyano, C₁₋₈ alkyl, C₁₋₈alkoxy, C₁₋₈ fluoroalkyl, C₁₋₈ fluoroalkoxy, phenyloxy or phenyl-C₁-C₈alkylene; and Y₃ is phenyl optionally substituted by one or moresubstituents selected from Y₂ which are identical to or different fromone another; or a salt thereof.
 4. The compound of formula (I) accordingto claim 1, wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; R₁ and R₂ areindependently of one another hydrogen or C₁₋₃ alkyl; or R₁ and R₂together form a group —(CH₂)_(p)—, where p is an integer ranging from 1to 5 such that n+p is an integer ranging from 2 to 5; or a salt thereof.5. The compound of formula (I) according to claim 1, wherein m is 0, 1,2 or 3; n is 0, 1, 2 or 3; R₁ and R₂ together form a group —(CH₂)_(p)—,where p is an integer ranging from 1 to 4 such that n+p is equal to 4;or a salt thereof.
 6. The compound of formula (I) according to claim 1,wherein X is oxygen; or a salt thereof.
 7. The compound of formula (I)according to claim 1, wherein R₃ is hydrogen; or a salt thereof.
 8. Aprocess for preparing a compound of formula (I) according to claim 1,comprising the step of reacting a compound of formula (IV)

wherein Y, X, R₁, R₂, R₃, R₅, m and n are as defined according to claim1 and R is methyl or ethyl, with an amine of formula R₆NH₂ where R₆ isas defined in formula (I) according to claim
 1. 9. A pharmaceuticalcomposition comprising at least one compound of formula (I) according toclaim 1, or a pharmaceutically acceptable salt thereof, in combinationwith one or more pharmaceutically acceptable excipients.